Girard Avenue was named for banker Stephen Girard (1750–1831) – at his death, the richest man in the United States[2] – who directed that his fortune be used to found a trade school for orphaned boys.

The first "Girard Avenue" was a 3-block street in North Philadelphia, between the 1800-block of Ridge Avenue and Corinthian Avenue, approaching the under-construction Girard College (confirmed by 1845). By 1852, the avenue had been extended west to 33rd Street; and in 1855, the timber-arched Girard Avenue Bridge carried it over the Schuylkill River and into West Philadelphia. To the east: In 1858, the name "Girard Avenue" was adopted for the existing Franklin Street, that ran east-west between 6th Street and Frankford Avenue; and for the existing Prince Street, that ran northeast-southwest between Frankford Avenue and Norris Street. The 12-block gap between 6th and 18th Streets was filled in before the Civil War.[3] The West Philadelphia section of the avenue was extended to 64th Street in 1868; and to 67th Street in 1936.[4]

In 1844, the area surrounding 2nd Street and Franklin Street (later Girard Avenue) was the site of several days of anti-Catholicnativist riots. Beginning May 3, the anti-immigrant American Republican Party held rallies in the Irish Catholic neighborhood of Kensington, provoking violence from its residents. Nativists responded by vandalizing houses and businesses owned by Catholics. Residents defended themselves with guns. Following several deaths, the Pennsylvania militia took control, but nativists returned in even larger numbers. The rioting reached its peak on May 8, when St. Michael's Church and its rectory, a Catholic school, and dozens of houses and businesses were burned. As the state militia struggled to regain control in Kensington, another nativist mob burned St. Augustine's Church in the Old City neighborhood.[5] In all, more than 14 people were killed, an estimated 50 were injured, and more than 200 were forced to flee their homes. The Kensington riots may have been more anti-Irish than anti-Catholic — the nativists did not attack the German Catholic church under construction at 5th Street and (what would become) Girard Avenue.[6]

The major landmark of Girard Avenue in North Philadelphia is Girard College, a boarding school for underprivileged children. The avenue merges with South College Avenue between 19th and 25th Streets to bypass the school's 43 acre (17 ha) campus. Girard Avenue Historic District – located between the school and Broad Street – features architecturally significant residential and religious buildings. Girard Avenue West Historic District – located between the school and 29th Street – features architecturally significant commercial and residential buildings. Brewerytown Historic District – located between 30th Street and East Fairmount Park – features architecturally significant residential and industrial buildings.

Girard Avenue east of Broad Street was a major shopping and entertainment district for lower North Philadelphia. Most of the late-19th and early-20th century theaters have been demolished, and surviving ones have been converted to other uses.

The Girard Avenue Trolley (SEPTA Route 15) follows a circuit from West Philadelphia to Kensington. A trolley begins the route at the Haddington Loop at 63rd Street, runs on the eastbound tracks along Girard Avenue, crosses the Girard Avenue Bridge, continues across North Philadelphia to Frankford Avenue, makes a 45-degree turn onto East Girard Avenue, follows that for a mile (East Girard Avenue ends), and completes the route along Richmond Street. At Westmoreland Street, the trolley makes a 180-degree turn around the Richmond-Westmoreland Streets Loop, and begins a return on the westbound tracks.

U.S. Route 13 runs northward along 34th Street (by the Philadelphia Zoo), merges with Girard Avenue to cross the Schuylkill River (via the Girard Avenue Bridge), then splits to continue northward along 33rd Street.

The proposed Girard Avenue Expressway – a below-grade superhighway that would have connected Interstate 95 (Delaware Expressway) with Interstate 76 (Schuylkill Expressway) and continued through West Philadelphia to the city line – was abandoned in 1977 following public opposition.[13]